Willow

Willow Bark (Salix spp.)

1. Identity: Botanical Classification, Sources, and Preparations

Taxonomy and Botanical Description

There are about 500 species of Salix called willow, mainly found in Europe and North America. The genus belongs to the family Salicaceae. The species of medical interest include Salix alba (white willow), S. nigra (black willow), and S. purpurea (purple willow), but S. daphnoides and S. fragilis along with S. purpurea contain the greatest yield of salicylate precursors. Although they are of different species, Salix alba and Salix nigra are often used interchangeably due to their strikingly similar uses and composition.

The Chinese used poplar tree (Populus alba L.) barks and willow (Salix babylonica L.) shoots for centuries, which reflects the breadth of medicinal species historically employed across cultures.

Pharmacopoeial Definition

According to the European Pharmacopoeia (01/2005:1583), the herbal substance is the whole or fragmented dried bark of young branches or whole dried pieces of current year twigs of various species of the genus Salix, including S. purpurea L., S. daphnoides Vill., and S. fragilis L. The drug contains not less than 1.5% of total salicylic derivatives, expressed as salicin (C₁₃H₁₈O₇; MW 286.3).

According to the Monograph of the European Pharmacopoeia and the Evaluation Report of the European Medicines Agency, the content of salicin derivatives in the bark of different species of willow varies from 0.5 to 10%.

Common Forms and Preparations

Willow bark is the common name for the dried bark of various Salix species. The EMA's HMPC conclusions cover willow bark preparations which are obtained by comminuting (reducing into tiny pieces) or powdering the bark and as dry or liquid extracts. Extracts are obtained by putting the plant material in a solvent (such as ethanol or water) to dissolve compounds. Additional traditional preparations include decoctions and teas; DAB 10 and related references recommend 2–3 g of herbal substance (finely chopped or coarsely powdered) 3 to 4 times per day. Standardized dry extracts are the most common form employed in contemporary clinical research, quantified by their total salicin content.

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2. Traditional and Historical Use

Ancient Mesopotamia and Egypt

The historical account of willow (Salix sp.) goes back to early civilizations, particularly in Mesopotamia, around 6000 years ago, when plants were exploited for food and as a source of drugs. Medical texts dating back to the ancient civilization of Sumer contain the oldest references to the beneficial effects of tea made from willow bark. In ancient times, the Egyptians and other cultures were believed to have used willow tree leaves or bark for their analgesic effects.

Ancient Greece and Rome

Chinese and Greek civilizations also exploited willow bark more than 2000 years ago to alleviate fever and pain. The philosopher Hippocrates (460–370 BC) recommended chewing willow bark to patients suffering from high temperature and pain. He also prescribed a brew of willow leaves to ease the pains of childbirth. Around 500 years later (100 AD), the Greek physician Dioscorides prescribed willow bark to reduce the symptoms of inflammation, and the use of willow bark continued because of its analgesic and anti-inflammatory properties.

Traditional Chinese Medicine

The Chinese used willow (Salix babylonica L.) shoots for centuries to treat rheumatic fever, colds, haemorrhages, and goitre, and as a general antiseptic for wounds and abscesses.

Indigenous North American Use

Historical accounts and archaeological evidence indicate that Indigenous Peoples in North America really did use willow bark to treat aches, pains, and fevers long before 18th-century cleric Edward Stone introduced willow bark as a medicine in England. We now know that white willow bark contains salicin, a compound that has fever- and pain-reducing properties.

18th-Century European Rediscovery

The first scientific description of willow bark is frequently credited to Edward Stone. In 1763, Stone is said to have prescribed the bark to patients to relieve fever. In 1898, salicin was converted to acetylsalicylic acid and sold as Aspirin by the Bayer company.

Traditional Preparations and Purposes

Willow bark has been used for centuries as a treatment for pain, headache, and inflammatory conditions such as bursitis and tendinitis. Traditional preparations across cultures have included bark decoctions (boiling in water), infusions or teas, and direct chewing of the bark. The use of willow leaves for the treatment of inflammatory rheumatic diseases was already known to the Sumerians.

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3. Key Constituents and Active Compounds

Phenolic Glycosides (Salicinoids)

Salicin derivatives are the main constituents of willow bark and can be quantified as salicin equivalents. Salicin is the simplest and most common salicinoid compound; however, it is often found at low quantities depending on the willow hybrid. The characteristic constituents are derivatives of salicin, mainly salicortin, 2'-O-acetylsalicortin, and/or tremulacin.

Other salicinoids in willows are formed by the esterification of one or more hydroxyl groups of salicin with organic acids, such as benzoic acid in populin and 1-hydroxy-6-oxocyclohex-2-en-1-carboxylic acid in salicortin. Other small phenolic glycosides common in willow bark are picein (a glucoside of hydroxyacetophenone), salidroside (a glucoside of phenylethanoid), and derivatives of cinnamic alcohols such as triandrin and vimalin.

Polyphenols and Tannins

Other constituents include flavonoids and condensed tannins (8–20% of the bark). Proanthocyanidins constitute up to 20% of bark dry weight, and several flavonoids belonging to flavan-3-ols, flavonols, flavanones, and chalcones have also been characterized.

Lignans

Sisymbrifolin, a lignan derivative, has been isolated from the bark of S. alba L. More recently, pinoresinol, lariciresinol, secoisolariciresinol, 7-hydroxymatairesinol, medioresinol, and lariciresinol-sesquilignan were detected in the biomass of five willow species.

Proanthocyanidins

Highly purified proanthocyanidin fractions of Salix spp. extract have been reported to have antiviral and antibacterial activities. Overall, proanthocyanidins (condensed tannins) have been characterized by many biological effects, including antioxidant, antibacterial, antitumor, anticancer, neuroprotective, hypoglycemic, and lipid-lowering activities.

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4. Mechanisms of Action

Metabolism of Salicin

β-d-Salicin, upon oral administration, is metabolized (which involves glycon hydrolysis and oxidation of benzyl carbon) in the gastrointestinal tract and bloodstream into the pharmacologically active form, salicylic acid. Salicylic acid was the major metabolite of salicin detected in serum (86% of total salicylates), besides salicyluric acid (10%) and gentisic acid (4%). Peak serum levels were reached within less than 2 hours after oral administration.

Willow Bark Is Not Equivalent to Aspirin

Willow species contain only a low quantity of the prodrug salicin which is metabolized during absorption into various salicylate derivatives. If calculated as salicylic acid, the daily salicin dose is insufficient to produce analgesia. Salicylic acid concentrations following an analgesic dose of aspirin are an order of magnitude higher. This distinction is confirmed by pharmacokinetic data: peak serum levels of salicylic acid were on average 1.2 mg/l, and the observed area under the serum concentration–time curve (AUC) of salicylic acid was equivalent to that expected from an intake of only 87 mg acetylsalicylic acid. Willow bark extract in the current therapeutic dose therefore leads to much lower serum salicylate levels than observed after analgesic doses of synthetic salicylates. The formation of salicylic acid alone is unlikely to explain the analgesic or anti-rheumatic effects of willow bark.

Role of Polyphenols and Broader Anti-inflammatory Mechanisms

Flavonoids and polyphenols contribute to the potent willow bark analgesic and anti-inflammatory effect. The multi-component active principle of willow bark provides a broader mechanism of action than aspirin. This is further supported by in vitro data: whereas a Salix extract potently prevented PGE₂ and cytokine release in a dose of 100 µg/mL, similar doses of salicin and salicylic acid alone showed no or only slight inhibitory effects, suggesting other constituents are responsible for the extract's effectiveness.

These compounds have been identified to exert a modulating role in inflammatory processes through inhibition of the activation of NF-κB and downregulation of COX-2 expression. Additionally, in 2013, Knuth and colleagues identified catechol as another important in vivo metabolite of willow bark compounds containing a 1-hydroxy-6-oxo-2-cyclohexenecarboxylate (HCH) moiety, such as salicortin.

Salicylic acid, the active metabolite of salicin, is highly protein-bound in the bloodstream and has a relatively large volume of distribution. It can penetrate various tissues, including the liver, kidneys, and synovial fluid, and may accumulate in inflamed tissues. Salicylic acid undergoes extensive metabolism primarily in the liver through processes such as glucuronidation and oxidation, leading to the formation of various metabolites. Some of these metabolites, such as salicyluric acid and gentisic acid, are further eliminated through the kidneys in the urine.

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5. Scientific Evidence by Area of Use

5.1 Acute Low Back Pain

Low back pain is the indication with the strongest body of clinical evidence and is recognized by the European Medicines Agency as an established use.

Key RCT (Chrubasik et al., 2000, American Journal of Medicine): Patients with exacerbations of low back pain were randomly assigned to receive an oral willow bark extract with either 120 mg (low dose) or 240 mg (high dose) of salicin, or placebo, with tramadol as the sole rescue medication, in a 4-week blinded trial. The principal outcome measure was the proportion of patients who were pain-free without tramadol for at least 5 days during the final week. This study confirmed that willow bark extract standardized to yield 240 mg of salicin is effective in treating pain.

Comparative study vs. rofecoxib (Chrubasik et al., 2001, Rheumatology): This study compared the effects of a proprietary extract of willow bark (Assalix) and a selective inhibitor of the enzyme COX-2 (rofecoxib). An open, randomized, post-marketing study was carried out in an out-patients clinic on two groups presenting with acute exacerbations of low back pain.

Systematic review (Vlachojannis et al., 2009, Phytotherapy Research): Seven manuscripts were identified, reporting four trials with confirmatory and four with exploratory study designs. Three manuscripts presented the same trial data and were excluded as repetitious reports. One confirmatory and two exploratory studies indicate a dose-dependent analgesic effect not inferior to rofecoxib in patients with low back pain.

Regulatory recognition: The European Medicines Agency (EMA) published a monograph for Salix cortex (various species including S. purpurea, S. daphnoides, and S. fragilis) based on well-established and traditional uses. The EMA monograph sets a daily dose for the willow bark extract (DER of 8–14:1, 15% total salicin content) of 393 to 1572 mg extract, corresponding to not more than 240 mg salicin (single ingredient preparation) for a duration of not more than 4 weeks, for short-term treatment of low back pain.

NCCIH assessment: In spite of its long history of use, only a few small clinical trials have been conducted that support the use of willow bark extracts in chronic low back pain and osteoarthritis. The overall evidence base is therefore described as limited in scope but directionally consistent for short-term low back pain relief.

5.2 Osteoarthritis

The evidence for osteoarthritis (OA) is more mixed than that for low back pain.

Schmid et al. (2001, Phytotherapy Research): This study assessed the clinical efficacy of a chemically standardized willow bark extract in the treatment of osteoarthritis. Willow bark extract, in a dose corresponding to 240 mg salicin per day, was compared with placebo in a 2-week, double-blind, randomized controlled trial. The primary outcome measure was the pain dimension of the WOMAC Osteoarthritis Index. Secondary outcome measures included the stiffness and physical function dimensions of the WOMAC, daily visual analogue scales on pain and physical function, and final overall assessments by both patients and investigators. A total of 78 patients (39 willow bark extract, 39 placebo) participated in the trial. A statistically significant difference between the active treatment and the placebo group was observed in the WOMAC pain dimension (d = 6.5 mm, 95% CI = 0.2–12.7 mm, p = 0.047); the WOMAC pain score was reduced by 14% from the baseline level after 2 weeks of active treatment, compared with an increase of 2% in the placebo group.

Biegert et al. (2004, Journal of Rheumatology): This study investigated the efficacy and safety of a standardized willow bark extract in patients with osteoarthritis (OA) and rheumatoid arthritis (RA), studying 127 outpatients with hip or knee OA and a WOMAC pain score of at least 30 mm and 26 outpatients with active RA in two randomized, controlled, double-blind trials with follow-up for 6 weeks. WOMAC pain scores decreased by 8 mm (17%) in the willow bark group and by 23 mm (47%) in the diclofenac group, compared with 5 mm (10%) in the placebo group. The OA study suggested that the willow bark extract showed no relevant efficacy in patients with OA. Similarly, the RA trial did not indicate efficacy of this extract in patients with RA.

2009 systematic review findings on OA: In one exploratory and one confirmatory study, conflicting results were achieved in participants with osteoarthritis. The evidence for osteoarthritis and related joint-discomfort settings is more limited and mixed.

2023 meta-analysis (Lin et al., Life): This study included five studies with six RCTs consisting of 329 patients with arthritis. The results showed significant differences in pain relief and improvement in physical status for patients with arthritis between willow bark treatment and placebo groups. However, although no significant differences in the risk of adverse events were found between willow bark treatment and placebo, owing to potential bias, the certainty and evidence of the findings are still inadequate. Therefore, further RCTs are needed to confirm these results.

5.3 Rheumatoid Arthritis

In the RA trial by Biegert et al. (2004), the mean reduction of pain on the VAS was −8 mm (15%) in the willow bark group compared with −2 mm (4%) in the placebo group. The difference was not statistically significant (estimated difference −0.8 mm; 95% CI −20.9 to 19.3 mm; p = 0.93). The evidence for RA is currently insufficient to support a clinical recommendation.

5.4 Fever and Headache

Traditional uses such as headache and fever linked with the common cold are still referenced, but they do not carry the same level of modern clinical support as the lower-back-pain indication recognized in official European references. No dedicated randomized controlled trials for these indications were identified in the available literature. These uses are classified as traditional use under the EMA framework rather than well-established use.

5.5 Antimicrobial and Antiviral Activity

Evidence in this domain is preclinical. Salicinoids of willow bark can decompose into salicylic acid, which has been found to possess anti-inflammatory and antiviral properties. Highly purified proanthocyanidin fractions of Salix spp. extract have been reported to have antiviral and antibacterial activities. These findings are preliminary and have not been confirmed in human clinical trials.

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6. Body Systems and Health Areas

• Musculoskeletal system: Willow bark extract is commonly employed as a complementary therapy for pain and inflammation management, such as those related to low back pain, osteoarthritis, tendinitis, bursitis, and headaches.
• Immune and inflammatory pathways: The extract modulates prostaglandin E₂ and cytokine release, and exerts a modulating role in inflammatory processes through inhibition of NF-κB activation and downregulation of COX-2 expression.
• Hepatic and renal systems: Salicylic acid, the principal active metabolite, is highly protein-bound and has a large volume of distribution, penetrating tissues including the liver and kidneys. It is primarily cleared renally after hepatic conjugation.
• Coagulation: An extract dose containing 240 mg salicin had no major impact on blood clotting, distinguishing willow bark from aspirin at standard therapeutic doses.

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7. Dosage Forms and Doses Reported in Studies

Dry Bark (Traditional)

DAB 10 and related German pharmaceutical references recommend 2–3 g of herbal substance (finely chopped or coarsely powdered) 3 to 4 times per day. Other references recommend 1–3 g of dry bark for decoction, three times daily.

Standardized Dry Extract (Clinical Studies)

Clinical trials have consistently employed extracts standardized to yield a defined quantity of salicin per day:

• Low-back-pain RCT (Chrubasik et al., 2000): oral willow bark extract with either 120 mg (low dose) or 240 mg (high dose) of salicin, over a 4-week blinded trial.
• Osteoarthritis RCT (Schmid et al., 2001): willow bark extract corresponding to 240 mg salicin per day, compared with placebo in a 2-week, double-blind, randomized controlled trial.
• RA trial (Biegert et al., 2004): patients were randomized to receive willow bark extract corresponding to 240 mg salicin per day or placebo; the main outcome measure was the patient's assessment of pain rated on a 100 mm visual analog scale.
• Pharmacokinetic study (Schmid et al., 2001): willow bark extract corresponding to 240 mg salicin (1,360 mg, 838 µmol) was ingested by ten healthy volunteers in two equal doses at times 0 h and 3 h.

EMA Monograph Dose

The EMA monograph sets a daily dose for willow bark extract (DER of 8–14:1, 15% total salicin content) of 393 to 1572 mg extract, corresponding to not more than 240 mg salicin (single ingredient preparation) for a duration of not more than 4 weeks.

Clinical studies show that willow bark extracts, typically delivering 120–240 mg salicin daily for up to 8 weeks, are generally safe for adults, with no reports of serious adverse effects.

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8. Safety: Adverse Effects, Contraindications, and Drug Interactions

General Tolerability

The multi-component active principle of willow bark is devoid of serious adverse events. In contrast to synthetic aspirin, willow bark does not damage the gastrointestinal mucosa. Reports from clinical trials primarily document GI discomfort (e.g., nausea, stomachache) as well as dizziness and skin rash. An anaphylactic reaction to willow bark has been reported.

Salicylate Burden and Regulatory Labeling

Metabolism of 240 mg salicin from willow bark could yield 113 mg of salicylic acid, yet dietary supplement products are not required to be labeled with warnings. In contrast, over-the-counter low-dose aspirin (81 mg strength), which delivers 62 mg salicylic acid, is required by law to include cautions, warnings, and contraindications related to its use in pregnant and nursing women, children, and other vulnerable subpopulations. In the interest of protecting public health, the United States Pharmacopeia has included a cautionary labeling statement in the USP Salix Species monograph: "Not for use in children, women who are pregnant or nursing, or by persons with known sensitivity to aspirin."

Contraindications (EMA Monograph)

The EMA Community Herbal Monograph on Salix cortex lists the following contraindications:

• Hypersensitivity to the active substance; hypersensitivity to salicylates or to other NSAIDs; asthma due to sensitivity to salicylates.
• Active peptic ulcer disease; pregnancy and lactation.
• Severe liver or renal dysfunction; coagulation disorders.

Duration of Use

Not to be used for more than 4 weeks, according to the EMA monograph. No case of overdose has been reported.

Use in Children

Willow bark should not be used in children and adolescents under the age of 18 years, as it has been associated with the risk of Reye's syndrome, a rare but serious condition that affects the liver and brain, when used during viral infections such as influenza or chickenpox.

Drug Interactions

In general, drug interactions associated with salicylates may apply to willow-containing products; however, the actual salicylate content of willow species is likely low.

• Anticoagulants: Specific preclinical data on interactions with other substances are not available. Nevertheless, a warning in case of concomitant use with anticoagulants is recommended in the EMA monograph. White willow may enhance the anticoagulant effect of warfarin.
• Other salicylates and NSAIDs: Potential additive irritant effects, including GI tract and platelet function adverse reactions, may occur with alcohol, barbiturates, sedatives, and other salicylate-containing products.
• Additional agents: Willow bark may also interact with oral anticoagulants, methotrexate, metoclopramide, phenytoin, probenecid, spironolactone, and valproate.
• Acetazolamide: Willow bark contains salicin, a plant salicylate. Human case reports suggest a combination of acetazolamide and salicylate can increase unbound plasma levels of acetazolamide as well as adverse effects related to acetazolamide.

Reproductive and Genotoxic Safety Data

Non-clinical information on the safety of willow bark preparations is scarce. Tests on reproductive toxicity, genotoxicity, and carcinogenicity have not been performed. As there is no information on reproductive and developmental toxicity, use during pregnancy is not supported.

Anaphylaxis

Anaphylaxis has been attributed to willow bark in a 25-year-old woman with a history of salicylate allergy who took a herbal slimming aid containing willow bark. Patients with a known hypersensitivity or allergy to aspirin or other salicylates should avoid willow bark, as it may trigger an allergic reaction.

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Summary of Evidence Strength

• Low back pain (short-term): Moderate evidence from multiple small to medium-sized RCTs and a systematic review. Recognized by the EMA as a well-established use at doses up to 240 mg salicin/day for up to 4 weeks. NCCIH characterizes the overall trial base as small.
• Osteoarthritis: Mixed evidence — one small RCT showed a modest, statistically significant benefit; a larger, longer-duration RCT found no statistically significant difference vs. placebo. A 2023 meta-analysis pooling 329 patients across 6 RCTs found aggregate significant differences in pain relief but rated overall certainty as inadequate.
• Rheumatoid arthritis: One small RCT with non-significant results. Insufficient evidence.
• Fever, headache, and other traditional uses: Supported by traditional use classification only; no controlled clinical trial evidence in these indications.
• Antimicrobial and antiviral activity: Preclinical (in vitro) evidence only.

References

• European Medicines Agency — Final Assessment Report on Salix [various species], cortex
• European Medicines Agency — EU Herbal Monograph on Salix cortex (final version)
• NCCIH — Nutritional Approaches for Musculoskeletal Pain and Inflammation: What the Science Says
• Vlachojannis JE, Cameron M, Chrubasik S. A systematic review on the effectiveness of willow bark for musculoskeletal pain. Phytotherapy Research. 2009;23(7):897–900.
• Chrubasik S et al. Treatment of low back pain exacerbations with willow bark extract: a randomized double-blind study. American Journal of Medicine. 2000;109(1):9–14.
• Schmid B et al. Efficacy and tolerability of a standardized willow bark extract in patients with osteoarthritis: randomized placebo-controlled, double blind clinical trial. Phytotherapy Research. 2001;15(4):344–350.
• Biegert C et al. Efficacy and safety of willow bark extract in the treatment of osteoarthritis and rheumatoid arthritis: results of 2 randomized double-blind controlled trials. Journal of Rheumatology. 2004;31(11):2121–2130.
• Lin CR et al. Willow Bark (Salix spp.) Used for Pain Relief in Arthritis: A Meta-Analysis of Randomized Controlled Trials. Life. 2023;13(10):2058.
• Schmid B et al. Pharmacokinetics of salicin after oral administration of a standardised willow bark extract. European Journal of Clinical Pharmacology. 2001;57(5):387–391.
• Vlachojannis J, Magora F, Chrubasik S. Willow species and aspirin: different mechanism of actions. Phytotherapy Research. 2011;25(7):1102–1104.
• Identification of Salicylates in Willow Bark (Salix Cortex) for Targeting Peripheral Inflammation. PMC / Frontiers in Pharmacology. 2021.
• Frontiers in Pharmacology — Phytochemistry, Pharmacology and Medicinal Uses of Plants of the Genus Salix: An Updated Review. 2021.
• Frontiers in Bioengineering and Biotechnology — Salix spp. Bark Hot Water Extracts Show Antiviral, Antibacterial, and Antioxidant Activities. 2021.
• PMC — The historical analysis of aspirin discovery, its relation to the willow tree and antiproliferative and anticancer potential. 2019.
• United States Pharmacopeia Safety Review of Willow Bark. 2019.
• Drugs.com Natural Product Database — Willow Bark: Uses, Benefits & Dosage (citing Barnes 2007; Vlachojannis 2011; Shalansky 2007)
• Chrubasik S et al. Treatment of low back pain with a herbal or synthetic anti-rheumatic: a randomized controlled study. Rheumatology (Oxford). 2001;40(12):1388–1393.